1. Field of the Invention
This invention relates to the controlled formation of particulate products using supercritical fluids. It provides a method and apparatus for the formation of a substance in particulate form, and the particulate product of such a method.
2. Description of Prior Art
The use of supercritical fluids (SCFs) and the properties thereof have been extensively documented; see for instance J. W. Tom and P. G. Debenedetti, "Particle Formation with Supercritical Fluids--A Review", J. Aerosol. Sci., 22 (5), pp555-584 (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. Such fluids have been of considerable interest, because of their unique properties. These characteristics include:
High diffusivity, low viscosity and low surface tension compared with liquids. PA1 High compressibility compared with the ideal gas implies large changes in fluid density with only slight changes in pressure, which in turn results in highly controllable solvation power. Supercritical fluid densities typically range from 0.1-0.9 g/ml under normal working conditions. Thus, selective extraction with one supercritical fluid is possible. PA1 Many supercritical fluids are normally gases under ambient conditions, which eliminates the evaporation/concentration step needed in conventional liquid extractions. PA1 Most of the commonly used supercritical fluids create non-oxidizing or non-degrading atmospheres for sensitive and thermolabile compounds, due to their inertness and the moderate temperatures used in routine working conditions. Carbon dioxide is the most extensively used SCF due to its cheapness, non-toxicity, non-flammability and low critical temperature.
These characteristics have led to the development of several techniques of extraction and particle formation utilising supercritical fluids. In particular, two particle formation methods have been identified.
"Rapid expansion of supercritical solution" (RESS) (see, for instance, J. W. Tom and P. G. Debenedetti, supra) involves the dissolution of the solute of interest in a supercritical fluid, followed by rapid expansion of the resulting supercritical solution to atmospheric pressure, resulting in the precipitation of solute particles.
"Gas anti solvent" (GAS) recrystallisation (P. M. Gallagher et al, "Supercritical Fluid Science and Technology", ACS Symp. Ser., 406, p334 (1989)) is particularly useful in situations when the solute of interest does not dissolve in, or has a very low solubility in, a supercritical fluid or a modified supercritical fluid. In this technique, the solute is dissolved in a conventional solvent. A supercritical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of its volume. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of particles.
The concept of spraying liquid mixtures into supercritical fluids such as carbon dioxide, or vice versa, has also been employed in solvent extraction procedures for a decade (see for instance R. J. Lahiere & J. R. Fair in Ind. Eng. Chem. Res., 26, pp2086-2092 (1987)).
More recently, U.S. Pat. No. 5,043,280 describes a method for manufacturing a preparation comprising a substance, such as a medically useful substance, and a carrier, such as a pharmaceutically acceptable carrier, which avoids or lacks a solvent residue, or at least reduces the solvent residue to a toxicologically harmless amount. The method essentially involves the use of a fluid, at a supercritical state when introduced into a spray tower, to extract a solvent from sprayed solution(s) of a substance and a carrier, to form a sterile product containing the substance embedded in the carrier. It should be noted, however, that the method has no means for controlling the physical properties of the particulate product formed.
In many fields, and especially in the fields of pharmaceuticals, photographic materials, ceramics, explosives and dyes, there is a need for techniques whereby a particulate product may be obtained with consistent and controlled physical criteria, including particle size and shape, quality of the crystalline phase, chemical purity and enhanced handling and fluidizing properties.
In addition, it would be advantageous to be able to prepare micron-sized particles directly, without the need to mill products to that size range. Such milling can lead to associated problems such as increased static charge and enhanced particle cohesiveness, as well as reduced product yield.
A further method for forming particulate products using supercritical fluids has been described more recently in our co-pending PCT patent application, no.
PCT/GB94/01426 of Jun. 30, 1994, which claims priority from UK patent application no. 9313650.5 of Jul. 1, 1993 and was published as WO-95/01221. In the method described in that patent application, a substance to be produced in particulate form is dissolved or suspended in an appropriate vehicle. The resulting solution or suspension is then co-introduced into a particle formation vessel with a supercritical fluid (preferably through a co-axial nozzle) in such a way that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid, and substantially immediately on introduction of the fluids into the vessel. The pressure and temperature inside the particle formation vessel are carefully controlled during this process.
This method allows a high degree of control over conditions such as pressure and temperature and fluid flow rates, at the exact point where particle formation occurs (i.e. at the point where the vehicle is extracted into the supercritical fluid). It therefore allows great control over the size and shape of the particles formed, and over other physical and/or chemical properties of the particles, including the polymorphic form where several are possible. The method is thus ideal for producing particles for use in fields where such high levels of control are necessary, for instance in the manufacture of pharmaceuticals, photographic materials, ceramics, etc. The method obviates the need for milling particulate products to a desired size range, thus eliminating the disadvantages of increased static charge, enhanced particle cohesiveness and reduced product yield, described above.
The applications of this and other particle formation techniques using supercritical fluids are, however, limited. The vehicle chosen must be soluble in the chosen supercritical fluid. Also, the substance itself, from which particles are to be formed, must be capable of dissolution, or at least suspension, in the chosen vehicle. It is not always easy to select a vehicle that can both dissolve the substance and also itself dissolve in the supercritical fluid being used (in practice, usually carbon dioxide).
An example of a situation in which such problems arise is the preparation of lactose. Lactose is commonly used as a carrier for pharmaceuticals, in tablets and capsule formulations and in particular for drugs to be delivered by inhalation methods. It thus needs to be prepared in the form of particles which have, among other characteristics, a narrow size distribution, a high purity and an appropriate particle shape.
However, lactose has very low solubility in conventional organic solvents which might be used with supercritical carbon dioxide in known particle formation techniques. Lactose dissolves readily in water, but water will not dissolve in supercritical carbon dioxide. It has thus, previously, been very difficult to form lactose particles directly from aqueous solution using known supercritical fluid techniques (including that described in WO-95/01221), since the supercritical fluid (typically carbon dioxide) would not extract water from the aqueous solution, or would do it so slowly as to be impractical. Nevertheless, it would be generally desirable to be able to form lactose particles in the controlled manner that supercritical fluid techniques (in particular that described in WO-95/01221) would allow.
It is generally known that other sugars and many amino acids and proteins suffer from similar disadvantages to that of lactose, ie. they have very low solubility in organic solvents and supercritical fluids/modified supercritical fluids (see Stahl et al, "Dense Gas Extraction on a Laboratory Scale: A Survey of some Recent Results", Fluid Phase Equilibria, 10, p269, 1983) and cannot therefore be formed into particles using former supercritical fluid particle formation techniques (RESS in particular). Again, as with lactose, it would be desirable to be able to produce particulate forms of such compounds in a controlled manner, for instance for use in pharmaceuticals and foodstuffs.
A related problem arises with many proteins. Although solutions of such proteins in organic solvents can be prepared, it is generally undesirable to do so because of the risk of the protein unfolding and denaturing (see, for instance, K. A. Dill & D. Shortle, Ann. Rev. Biochem., 1991, 60, pp795-825, especially p813) Thus, it is difficult if not impossible, to prepare. particulate products of such proteins, with acceptable biological activity, using known supercritical fluid particle formation techniques.
There are many other examples of substances which might otherwise be formed into particles using supercritical fluids, but which cannot be sufficiently well dissolved or suspended in an appropriate solvent which will itself dissolve in a useful supercritical fluid.
There is therefore a need to solve this problem, to allow the use of supercritical fluid particle formation techniques (including the extremely effective technique described in WO-95/01221) for substances such as lactose. and proteins. The present invention sets out to overcome, or at least mitigate, the problem.